Abstract Neuroimaging has expanded our understanding of brain development from childhood into early adulthood. Adolescent substance use trends have shifted over time, but use of cannabis, alcohol, and tobacco remain prevalent, typically starting during teenage years, when serious mental health conditions also tend to emerge. Although physical health is at its lifetime peak, emerging concerns for teens include increasing rates of depression, anxiety, social isolation, suicidal ideation, and excessive use of screen media. The extent to which early substance use and other environmental exposures may place youth at risk for altered neurodevelopment and adverse outcomes remains poorly understood. A diverse sample of 11,878 9-10 year olds was enrolled from 21 sites across the ABCD Study consortium, and 554 were enrolled at Virginia Commonwealth University (VCU), under RFA-DA-15-015. All participants underwent a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, culture and environment, and mobile monitoring every 2 years. Interim in-person annual interviews and biannual telephone or mobile app assessments provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. Intensive efforts are made to retain the vast majority of participants through adolescence and beyond and retention rates thus far are very high. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental trajectories in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences affect brain development; (5) determine and replicate factors that influence the onset, course, and severity of mental illnesses; (6) characterize the relationship between mental health and substance use; and (7) specify how use of different substances (e.g., cannabis, alcohol, tobacco, caffeine) affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence substance use risk.